The invention relates to the use of low-dose photodynamic therapy (PDT) to inhibit or reduce stenosis caused by intimal hyperplasia (IH) in blood vessels. In particular, the treatment of IH at an anastomosis of a graft or conduit providing vascular access, such as an arteriovenous (AV) fistula, is disclosed. The invention also relates to inhibiting or reducing the smooth muscle cell (SMC) growth component of IH by low-dose PDT.
Patients with chronic renal failure in the United States number approximately 2 million, with 220,000 receiving dialysis therapy as of 1998 (1). The current annual increase in the number of patients receiving chronic hemodialysis is 6 to 7 percent due to acceptance of older candidates, patients living longer, the scarcity of transplantable kidneys, and the loss of transplanted kidneys, returning people to dialysis (1,2). Long-term dialysis requires provision of safe and reliable vascular access, often in the form of an arteriovenous (AV) fistula or an AV conduit, usually made of polytetrafluoroethylene (PTFE)(3,4,5). Unfortunately the failure rate of access fistulae can be as high as 60% at one year, with the mean time from insertion to first repair being only 10 months (6,7).
The primary cause of AV fistula or AV conduit loss or failure is stenosis caused by intimal hyperplasia (IH), which includes a smooth muscle cell (SMC) growth component, in the graft at the venous anastomosis or the distal vein (8). IH leads to formation of a thickened fibromuscular layer between the vein endothelium and the inner elastic lamina (IEL). Excessive thickening of the intima can lead to luminal narrowing and reduction of blood flow to such an extent that thrombosis occurs (9). This early failure represents the destruction of a useful access site, ultimately compromising the life of a patient dependent on dialysis (10). Mortality among dialysis patients, although slowly declining, remains at 20 percent per year (11).
Considerable research has aimed at pharmacological intervention to prevent intimal hyperplasia, and although a number of agents have shown great promise in animal or angioplasty modelsxe2x80x94very few have been shown to be of any benefit in hemodialysis patients (12). Photodynamic therapy (PDT) is an approach that has been investigated for the inhibition of intimal hyperplasia in other settings (see U.S. Pat. No. 5,422,362, which is hereby incorporated by reference). PDT generally involves administration of an inert photosensitizer (PS) that becomes activated by a specific wavelength of light. Once activated, PS produces toxic oxygen species that cause cell death by affecting cell membranes and subcellular organelles (13) or, when used in low doses, modulate cell behavior (14,15,16).
Intimal hyperplasia has been successfully inhibited in animal models involving balloon-catheter induced injury to arteries by PDT (17,18), and human SMCs isolated from arteries and veins have been shown to be susceptible to PDT (19,20). LaMuraglia et al. have investigated the efficacy of PDT to reduce vein graft IH. Although their xe2x80x9cex vivoxe2x80x9d PDT protocol led to suppression of IH in the body of the vein graft, it did not affect IH at the anastomosis of the vein graft to an artery (21).
The present invention relates to methods of using photodynamic therapy (PDT) to prevent, treat, inhibit or reduce intimal hyperplasia (IH) in blood vessels in vivo. In particular the methods may be applied to the in vivo prevention and/or treatment of stenosis in an anastomosis, such as at those of an arteriovenous (AV) fistula or conduit. The methods of the invention may be used in any vein, artery, and/or vascular graft, and include the combined use of a photosensitizer (PS) and radiation sources for irradiation that offer advantages over previous methods of treating blood vessels and anastomoses, including those of AV fistulae or conduits. The PS may be delivered systemically, locally, and even directly into the lumen of the blood vessel tissue to be treated. Local delivery of the PS provides a high local concentration while reducing the likelihood of transient skin photosensitivity that might follow systemic PS administration.
Following, or simultaneous with, PS administration, treatment with radiation absorbed by the PS may be performed by any means, including direct irradiation of the anastomosis, the blood vessel tissue containing it, or a larger area containing the anastomosis and other tissues, or extraluminal irradiation from the adventitia using ambient light or a flexible patch diffuser. In a preferred embodiment, the radiation is applied via a flexible patch diffuser that can be wrapped around the blood vessel. This permits the use of lower light intensities that inhibit IH inhibit (IH) without compromising the blood vessel""s wall.